The transmission of an infectious agent from one host to another is critical to the success of any pathogen. In the case of HIV, a successful transmission is dependent on the ability of the virus to transverse a mucosal membrane (rectal, penile, vaginal or oral) of a new host and establish a productive infection. This proposal builds on findings we obtained while undertaking a previous grant funded by the NIH (NIDCR) (1999 to 2003) to assess the earliest events following oral transmission of SIV in the macaque model. Oral transmission of HIV represents a major route of transmission from mother to infant, through ingesting the virus during breast-feeding;as well as in adults during oral genital transmission (virus in semen). One major finding from our previous studies was the identification of the oral mucosa, esophagus and tonsils as sites of SIV entry following a nontraumatic oral application of the virus and the assessment of the innate and adaptive immune responses that correlate with the rates of disease progression. Here we expand upon our previous findings by assessing the impact of immune activation on the transmission of SIV administered into the oral cavity. We hypothesize that higher levels of immune activation will increase the potential for SIV to elicit a productive infection when administered to the oral cavity of macaques. These studies will utilize a low dose regimen of viral inoculations to mimic the viral levels that are present in breast milk and semen. The goal of specific aim 1 is to determine the appropriate viral inoculum to undertake aim two, and to investigate the correlates of viral transmission in the absence of any immune modifications. Aim 2 will assess transmission of SIV while the mucosa is experiencing a state of immune activation, gingivitis. Gingivitis is a common inflammation of the oral mucosa in humans and therefore may be impacting oral transmission in humans exposed to HIV containing semen (through receptive oral intercourse). These studies assessing the impact of the immune response on oral transmission will likely be applicable to other sites of mucosal transmission, and will be important for determining the immune mechanisms that impact the success of SIV/HIV mucosal transmission. Our long term goal is to utilize these findings to aid in the design of SIV/HIV vaccines that are able to elicit sterilizing immunity by preventing the infection of the first target cell when mucosal sites are exposed to HIV/SIV.